IP2 and Regulatory Affairs

1. INVESTIGATOR BROCHURE
Venugopal N

2. Introduction
ICH E6: Good Clinical Practice
Section 7: Investigator’s Brochure
• The Investigator's Brochure (IB) is a compilation of the clinical
and nonclinical data on the investigational product(s) that are
relevant to the study of the product(s) in human subjects.
• Its purpose is to provide the investigators and others involved
in the trial with the information to facilitate their
understanding of the rationale for, and their compliance with,
many key features of the protocol, such as the dose, dose
frequency/interval, methods of administration: and safety
monitoring procedures.

3. • The IB also provides insight to support the clinical management
of the study subjects during the course of the clinical trial.
• The information should be presented in a concise, simple,
objective, balanced, and non-promotional form that enables a
clinician, or potential investigator, to understand it and make
his/her own unbiased risk-benefit assessment of the
appropriateness of the proposed trial.
• For this reason, a medically qualified person should generally
participate in the editing of an IB, but the contents of the IB
should be approved by the disciplines that generated the
described data.

4. Extent of information:
• If the investigational product is marketed and its pharmacology
is widely understood by medical practitioners, an extensive IB
may not be necessary.
• If a marketed product is being studied for a new use (i.e., a new
indication), an IB specific to that new use should be prepared.
The IB should be reviewed at least annually and revised as
necessary in compliance with a sponsor's written procedures.
The sponsor is responsible for ensuring that an up-to-date IB is
made available to the investigator(s) and the investigators are
responsible for providing the up-to-date IB to the responsible
IRBs/IECs.

5. General Consideration
Title Page:
• Sponsor name
• Identity of each investigational product (i.e., research number,
chemical or approved generic name, and trade name(s) where
legally permissible and desired by the sponsor)
• Release date.
Confidentiality Statement:
The sponsor may wish to include a statement instructing the
investigator/recipients to treat the IB as a confidential document
for the sole information and use of the investigator's team and the
IRB/IEC

7. Contents of IB
1. Table of Contents
2. Summary
3. Introduction
4. Physical, chemical and pharmaceutical properties &
formulation
5. Nonclinical studies
6. Effect in humans
7. Summary of Data and Guidance for the investigator

9. 2. Summary
• A brief summary (preferably not exceeding two pages) should
be given, highlighting the significant physical, chemical,
pharmaceutical, pharmacological, toxicological,
pharmacokinetic, metabolic, and clinical information available
that is relevant to the stage of clinical development of the
investigational product.

10. 3. Introduction
• A brief introductory statement should be provided that contains
the chemical name (and generic and trade name when
approved) of the investigational product, all active ingredients,
the investigational product pharmacological class and its
expected position within this class (e.g., advantages), the
rationale for performing research with the investigational
product, and the anticipated prophylactic, therapeutic, or
diagnostic indication.
• Finally, the introductory statement should provide the general
approach to be followed in evaluating the investigational
product.

11. Physical, Chemical, and Pharmaceutical
Properties and Formulation
• A description should be provided of the investigational product
substance (including the chemical and/or structural formula),
and a brief summary should be given of the relevant physical,
chemical, and pharmaceutical properties.
• To permit appropriate safety measures to be taken in the course
of the trial, a description of the formulation to be used,
including excipients, should be provided and justified if
clinically relevant. Instructions for the storage and handling of
the dosage form should also be given.
• Any structural similarities to other known compounds should
be mentioned.

12. 5. Nonclinical studies
• The results of all relevant nonclinical pharmacology, toxicology,
pharmacokinetic, and investigational product metabolism
studies should be provided in summary form.
• This summary should address the methodology used, the
results, and a discussion of the relevance of the findings to the
investigated therapeutic and the possible unfavorable and
unintended effects in humans.

13. The information provided may include the following,
as appropriate, if known/available:
• Species tested
• Number and sex of animals in
each group
• Unit dose
• Dose interval
• Route of administration
• Duration of dosing
• Information on systemic
distribution
• Duration of post-exposure
follow-up
• Results, including the following
aspects:
• Nature and frequency of
pharmacological or toxic effects
• Severity or intensity of
pharmacological or toxic effects
• Time to onset of effects
• Reversibility of effects
• Duration of effects
• Dose response

14. Nonclinical Pharmacology
Pharmacokinetics and Product
Metabolism in Animals
Toxicology

15. a. Nonclinical Pharmacology
• A summary of the pharmacological aspects of the
investigational product and, where appropriate, its significant
metabolites studied in animals, should be included.
• Such a summary should incorporate studies that assess
potential therapeutic activity (e.g., efficacy models, receptor
binding, and specificity) as well as those that assess safety (e.g.,
special studies to assess pharmacological actions other than the
intended therapeutic effect).

16. b. Pharmacokinetics and Product
Metabolism in Animals
• A summary of the pharmacokinetics and biological
transformation and disposition of the investigational product in
all species studied should be given.
• The discussion of the findings should address the absorption
and the local and systemic bioavailability of the investigational
product and its metabolites, and their relationship to the
pharmacological and toxicological findings in animal species.

17. c. Toxicology
A summary of the toxicological effects found in relevant studies
conducted in different animal species should be described under
the following headings where appropriate:
• Single dose
• Repeated dose
• Carcinogenicity
• Special studies (e.g., irritancy and sensitization)
• Reproductive toxicity
• Genotoxicity (mutagenicity)

18. 6. Effects in Humans
Introduction:
• A thorough discussion of the known effects of the
investigational product in humans should be provided,
including information on pharmacokinetics, metabolism,
pharmacodynamics, dose response, safety, efficacy, and other
pharmacological activities.
• Where possible, a summary of each completed clinical trial
should be provided.
• Information should also be provided regarding results of any
use of the investigational product other than from in clinical
trials, such as from experience during marketing.

19. Pharmacokinetics and Product
Metabolism in Humans
Safety and Efficacy
Marketing Experience

20. a. Pharmacokinetics and Product Metabolism in
Humans
A summary of information on the pharmacokinetics of the
investigational product should be presented, including the following:
• Pharmacokinetics (including metabolism, as appropriate, and
absorption, plasma protein binding, distribution, and elimination).
• Bioavailability of the investigational product using a reference dosage
form.
• Population subgroups (e.g., gender, age, & impaired organ function).
• Interactions (e.g., product-product interactions and effects of food).
• Other pharmacokinetic data (e.g., results of population studies
performed within clinical trial(s).

21. b. Safety and Efficacy
• A summary of information should be provided about the investigational
product's safety, pharmacodynamics, efficacy, and dose response that were
obtained from preceding trials in humans subjects.
• In cases where a number of clinical trials have been completed, the use of
summaries of safety and efficacy across multiple trials by indications in
subgroups may provide a clear presentation of the data.
• Tabular summaries of adverse drug reactions for all the clinical trials.
• Important differences in adverse drug reaction patterns/incidences across
indications or subgroups should be discussed.
• The IB should provide a description of the possible risks and adverse drug
reactions to be anticipated on the basis of prior experiences with the product
under investigation and with related products.
• A description should also be provided of the precautions or special
monitoring to be done as part of the investigational use of the product(s).

22. c. Marketing Experience
• The IB should identify countries where the investigational
product has been marketed or approved.
• Any significant information arising from the marketed use
should be summarized (e.g., formulations, dosages, routes of
administration, and adverse product reactions).
• The IB should also identify all the countries where the
investigational product did not receive approval/registration
for marketing or was withdrawn from marketing/registration.

23. 7. Summary of Data and Guidance for the
Investigator
• This section should provide an overall discussion of the
nonclinical and clinical data, and should summarize the
information from various sources on different aspects of the
investigational product, wherever possible.
• In this way, the investigator can be provided with the most
informative interpretation of the available data and with an
assessment of the implications of the information for future
clinical trials.
• Where appropriate, the published reports on related products
should be discussed.
• This could help the investigator to anticipate adverse drug
reactions or other problems in clinical trials.

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